The goals of this program are to use an interdisciplinary and collaborative approach to elucidate the roles and regulation of p53 and related proteins in tumorigenesis using biochemistry, cell based assays, mouse models, informatics and analysis of human tumors. Carol Prives will study the regulation of the p53 family by the checkpoint kinases 1 and 2, will characterize the interactions of p53 family members with newly identified proteins and with each other and will determine how different family members are regulated and interact with their target genes in DMA. Arnold Levine will identify and characterize the single nucleotide polymorphisms (SNP's) that are found in the genes which compose the p53 pathway in cells, and will utilize a previously designed algorithm to identify novel p53 target genes in the mouse and human genome. Scott Lowe will use the Ep. -myc transgenic model to determine how survival signaling through the PI3K/Akt pathway promotes chemoresistance in vivo, and how genes involved in apoptosis, senescence, and survival signaling influence p53 action and treatment outcome. He will also utilize the availability of RNAi libraries to identify new genes that influence chemotherapy outcome in this model. Carlos Cordon-Cardo will evaluate the predictive significance of alterations in the p53 pathway, p53 DNA damage response and the PTEN/AKT pathway in bladder cancers from human patients. Multiple collaborative projects between these different Principal Investigator's are planned that cannot be accomplished by any single investigator. This program will thus exploit the individual and combined expertise of four researchers who are using complementary approaches to develop a translational approach for treatment and diagnosis of cancer.